| Summary: | At present, the calculated binding free energy obtained using the molecular mechanics/Poisson-Boltzmann (Generalized-Born) surface area (MM/PB(GB)SA) method is overestimated due to the lack of knowledge of suitable interior dielectric constants in the simulation on the interaction of Human Immunodeficiency Virus (HIV-1) protease systems with inhibitors. Therefore, the impact of different values of the interior dielectric constant and the entropic contribution when using the MM/PB(GB)SA method to calculate the binding free energy was systemically evaluated. Our results show that the use of higher interior dielectric constants (1.4–2.0) can clearly improve the predictive accuracy of the MM/PBSA and MM/GBSA methods, and computational errors are significantly reduced by including the effects of electronic polarization and using a new highly efficient interaction entropy (IE) method to calculate the entropic contribution. The suitable range for the interior dielectric constant is 1.4–1.6 for the MM/PBSA method; within this range, the correlation coefficient fluctuates around 0.84, and the mean absolute error fluctuates around 2 kcal/mol. Similarly, an interior dielectric constant of 1.8–2.0 produces a correlation coefficient of approximately 0.76 when using the MM/GBSA method. In addition, the entropic contribution of each individual residue was further calculated using the IE method to predict hot-spot residues, and the detailed binding mechanisms underlying the interactions of the HIV-1 protease, its inhibitors, and bridging water molecules were investigated. In this study, the use of a higher interior dielectric constant and the IE method can improve the calculation accuracy of the HIV-1 system.
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